Combination antiretroviral therapy (cART) containing reverse transcriptase inhibitors (RTIs) can only attenuate HIV and HBV replication, and has marginal therapeutic effect on advanced liver diseases, a leading cause of morbidity and mortality in HIV-infected persons. The underlying mechanisms by which HBV-induced liver pathogenesis, and mechanisms by which HIV co-infection accelerate that process remain unknown due in large part to the lack of small animal models. We recently developed novel humanized mouse models carrying autologous human liver and immune system cells, which support viral hepatitis infections (HBV/HCV), HIV co- infections and associated liver diseases. Inflammation associated macrophages are mainly derived from circulating monocytes and represent a major component of the inflammatory milieu in many liver diseases; however, very little is known about their role in liver pathogenesis. Macrophages are broadly classified as M1 activated, which promote the Th1 associated anti-viral response, and M2-like activated which impair Th1 response and promote tissue pathology. We recently showed that chronic HBV/HCV-induced liver inflammation in both humanized mice and humans is associated with high levels of infiltrating M2-like macrophages which localized to fibrotic and neoplastic regions. Similar findings have been reported with other inflammatory diseases. HIV infection also results in increased M2-like macrophage activation in both humanized mice and humans. Our central hypothesis is that HIV accelerates liver disease in HBV/HIV co- infections by exacerbating M2-like macrophage pathogenesis in the liver. This proposal utilizes a novel humanized mouse model, and macrophage-hepatic stellate cell co-culture to address critical knowledge gaps on the role of macrophage activation in HBV/HIV co-infection and associated liver diseases. To elucidate the role of macrophage activation in HBV/HIV co-infection and associated liver pathogenesis, Specific Aim 1 will be to delineate the effect of HBV/HIV co-infection and associated anti-viral therapy on monocyte/macrophage activation and liver disease progression in the humanized mouse model. Specific Aim 2 will be to investigate the molecular basis by which macrophages modulate hepatic stellate cell activation and associated liver fibrogenesis in HBV/HIV co-infection using macrophage-hepatic stellate cell co-culture models and humanized mice. This work will elucidate the role of macrophages in HBV/HIV co-infection and associated liver pathogenesis, and lead to novel therapeutic strategies against inflammatory liver diseases.